Project Summary/Abstract We propose a pre-clinical study in rodent animal models of type 2 diabetes (T2D) characterized by obesity and insulin resistance, to determine if the orally-administered CXCR2 chemokine receptor inhibitor AZD5069 (Astra Zeneca) can: i) improve insulin sensitivity, glucose and insulin tolerance in pre-diabetic mice concurrent with prevention or delay in onset of hyperglycemia; ii) improve and stabilise insulin sensitivity in diabetic recipients; and iii) preserve and stabilise ? cell function in diabetic recipients. In addition, a series of mechanistic studies are proposed to further decipher the effects of CXCR2 inhibition on the regulation of neutrophil and macrophage populations in the key glucoregulating tissues of the rodent study population. This proposal is a consequence of a use case approach to identify phase II clinical trial-ready antagonists of the CXCR2 signaling pathway through querying and polling publically-available drug profile databases and open innovation crowdsourcing drug repositories. The study objectives/endpoints are built upon the hypothesis that CXCR2 inhibition impairs and interferes with neutrophil- and macrophage-orchestrated inflammation that underlies pre- clinical and clinical T2D. We propose three aims to realise our endpoints and to test our hypothesis. AZD5069 is an attractive agent considering the emerging data on the role of neutrophils in obesity-associated metabolic impairments characterized by systemic and glucoregulating tissue-selective inflammation. We believe that this study establishes a novel direction for T2D therapy and potentially for other inflammation-associated disorders of metabolism.